Heme oxygenase-2 (HO-2) binds and buffers labile ferric heme in human embryonic kidney cells.
Heme oxygenase-2 (HO-2) binds and buffers labile ferric heme in human embryonic kidney cells.
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DOI：
10.1016/j.jbc.2021.101549
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Reddi AR
中科院分区：
文献类型：
--
作者：
Hanna DA;Moore CM;Liu L;Yuan X;Dominic IM;Fleischhacker AS;Hamza I;Ragsdale SW;Reddi AR
血红素加氧酶（HOs）通过氧化将血红素分解为一氧化碳、铁和胆绿素来解毒，胆绿素被还原为胆红素并排出体外。人类表达HO的两种亚型：诱导型HO-1和组成型HO-2。诱导型HO-1在过量血红素和其他应激源的作用下上调。我们对HO-1的调控和生理功能了解甚多，而对HO-2在调节血红素稳态中的作用知之甚少。表达组成型HO-2的生化必要性取决于血红素是否足够丰富，并且在HO-1不被诱导的条件下作为底物是否可获得。通过测量HO-2沉默或过表达的人胚胎肾HEK293细胞以及各种HO-2突变等位基因中的不稳定血红素、总血红素和胆红素，我们发现内源性血红素是一种限制性底物，无法观察HO-2依赖性血红素降解。相反，我们发现了HO-2在血红素结合和缓冲中的新作用。综上所述，在没有过量血红素的情况下，我们提出HO-2通过作为血红素缓冲因子控制血红素的生物利用度来调节血红素稳态。当血红素过量时，HO-1被诱导，HO-2和HO-1都可以通过酶降解对血红素毒性提供保护。我们的研究结果解释了为什么催化失活的HO-2突变体对氧化应激具有细胞保护作用。此外，由于HO-2过表达导致的生物可利用血红素的变化，选择性地结合铁血红素和亚铁血红素，与不稳定血红素被氧化一致，从而为血红素运输和信号传导提供了新的见解。
Heme oxygenases (HOs) detoxify heme by oxidatively degrading it into carbon monoxide, iron, and biliverdin, which is reduced to bilirubin and excreted. Humans express two isoforms of HO: the inducible HO-1, which is upregulated in response to excess heme and other stressors, and the constitutive HO-2. Much is known about the regulation and physiological function of HO-1, whereas comparatively little is known about the role of HO-2 in regulating heme homeostasis. The biochemical necessity for expressing constitutive HO-2 is dependent on whether heme is sufficiently abundant and accessible as a substrate under conditions in which HO-1 is not induced. By measuring labile heme, total heme, and bilirubin in human embryonic kidney HEK293 cells with silenced or overexpressed HO-2, as well as various HO-2 mutant alleles, we found that endogenous heme is too limiting a substrate to observe HO-2-dependent heme degradation. Rather, we discovered a novel role for HO-2 in the binding and buffering of heme. Taken together, in the absence of excess heme, we propose that HO-2 regulates heme homeostasis by acting as a heme buffering factor that controls heme bioavailability. When heme is in excess, HO-1 is induced, and both HO-2 and HO-1 can provide protection from heme toxicity via enzymatic degradation. Our results explain why catalytically inactive mutants of HO-2 are cytoprotective against oxidative stress. Moreover, the change in bioavailable heme due to HO-2 overexpression, which selectively binds ferric over ferrous heme, is consistent with labile heme being oxidized, thereby providing new insights into heme trafficking and signaling.
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血红素加氧酶及其代谢物在心血管功能调节中的新作用。
影响因子：
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作者：
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